Estrogens, such as estradiol, have been well known for their promotion of rapid weight gain. As such, they have been commercially marketed as food additives, suitable for use in "fattening" animals more quickly. These additives have been used, for example, to increase weight in animals before they are slaughtered, in order to provide more meat from a single animal.
Donohoe and Stevens have published results which suggest that the mode of administration of estrogens may be responsible for the observed effects on weight. T. P. Donohoe, et al., Pharm. Biochem., 16, 93-99, 1982. Donohoe et al. implanted ovariectomized rats with crystalline estradiol benzoate, estrone or estriol using cannulae. This implantation was aimed at the ventromedial nucleus-arcuate region of the hypothalamus. Administration in this manner caused significant reduction in food intake and body weight for these rats, in contrast to the weight gain generally observed from the use of these compounds. In contrast, however, dorsal and lateral implantation of these compounds in the rats were generally ineffective in promoting weight loss. Thus, the effect of estradiol appears to be specific to the method of implantation. No oral administration was tested by Donohoe. Finally, it should be pointed out that these rats were ovariectomized animals, it can not be assumed that these results would be equally applicable to animals with intact ovaries.
The use of estrogens has significant drawbacks, as estrogens such as DES are known to be carcinogens and teratogens, and estradiol, when administered at therapeutic doses, is suspected to have carcinogenic properties. Thus, it was desirable to obtain compounds which mimicked the properties of the previously known estrogen compounds, without displaying the adverse side effects which they were known or suspected to possess.
Doisynolic acid compounds are known compounds which have been shown to have estrogenic properties in vitro. Meyers, et. al., J. Steroid Biochem, Vol. 31, pgs 393-404 (1988), herein incorporated by reference, discloses a variety of doisynolic acids. These compounds were found to exhibit no toxicity or carcinogenicity in mice, even though each of the doses which was administered was at least 1000 times the dose required for detectable estrogenic effects. In control studies, mice which were similarly treated with known carcinogens developed easily detected tumors. Meyers, J. Steroid Biochem, supra.